Novel compounds and their use

ABSTRACT

Compounds of the general formula (I):  
                 
 
     wherein R 1 , R 2 , R 3  and R 4  are as described in the specification.  
     Further included are pharmaceutical compositions comprising the compounds, processes for their preparation, as well as the use of the compounds for the preparation of a medicament which particularly acts on the central nervous system, particularly for use as anti-obesity agents.

RELATED APPLICATIONS

[0001] This application claims priority to Swedish application number0201544-4, filed on May 17, 2002, and U.S. provisional application60/410,038, filed on Sep. 12, 2002, the contents of which areincorporated herein by reference.

TECHNICAL FIELD

[0002] The present invention relates to novel compounds, topharmaceutical compositions comprising the compounds, to processes fortheir preparation, as well as to the use of the compounds for thepreparation of a medicament which particularly acts on the centralnervous system.

BACKGROUND ART

[0003] Many disorders and conditions of the central nervous system areinfluenced by the adrenergic, the dopaminergic, and the serotonergicneurotransmitter systems. For example, serotonin (5-HT;5-hydroxytryptamine) has been implicated in a number of disorders andconditions which originate in the central nervous system. A number ofpharmacological and genetic experiments involving receptors forserotonin strongly implicate the 5-HT_(2c) receptor subtype in theregulation of food intake, see for example Obes. Res. 1995, 3, Suppl. 4,449S-462S and Drugs Future 2001, 26, 383-393. The 5-HT_(2c) receptorsubtype is transcribed and expressed in hypothalamic structuresassociated with appetite regulation. It has been demonstrated that the5-HT_(2c) receptor agonist m-chlorophenylpiperazine (mCPP), which hassome preference for the 5-HT_(2c) receptor, reduces food intake in micethat express the normal 5-HT_(2c) receptor while the compound lacksactivity in mice expressing the mutated inactive form of the 5-HT_(2c)receptor (Nature 1995, 374, 542-546). In a recent clinical study, aslight but sustained reduction in body weight was obtained after 2 weeksof treatment with mCPP in obese subjects (Psychopharmacology 1997, 133,309-312). Recently, a series of pyrrolo[3,2,1-ij]quinoline derivativeswas identified to be 5-HT_(2c) receptor agonists having selectivity overthe 5-HT_(2a) receptor (Isaac M., et al., Bioorg. Med. Chem. Lett. 2000,10, 919-921). The compounds are said to offer a novel approach to thetreatment of obesity and epilepsy.

[0004] Weight reduction has also been reported from clinical studieswith other “serotonergic” agents (see e.g. IDrugs 1998, 1, 456-470). Forexample, the 5-HT reuptake inhibitor fluoxetine and the 5-HT releasingagent/reuptake inhibitor dexfenfluramine have exhibited weight reductionin controlled studies. However, currently available drugs that increaseserotonergic transmission appear to have only a moderate and, in somecases, transient effects on the body weight.

[0005] The 5-HT_(2c) receptor subtype has also been suggested to beinvolved in CNS disorders such as depression and anxiety (Exp. Opin.Invest. Drugs 1998, 7, 1587-1599; IDrugs, 1999, 2, 109-120).

[0006] The 5-HT_(2c) receptor subtype has further been suggested to beinvolved in urinary disorders such as urinary incontinence (IDrugs,1999, 2, 109-120).

[0007] Compounds which have an effect on the 5-HT_(2c) receptor maytherefore have a therapeutic potential in the treatment of disorderslike those mentioned above.

INFORMATION DISCLOSURE

[0008] U.S. Pat. No. 3,253,989 discloses the use of mCPP as an anorecticagent.

[0009] EP-A1-863 136 discloses azetidine and pyrrolidine derivativeswhich are selective 5-HT_(2c) receptor agonists having antidepressantactivity and which can be used for treating or preventingserotonin-related diseases, including eating disorders and anxiety.

[0010] EP-A-657 426 discloses tricyclic pyrrole derivatives havingactivity on the 5-HT_(2c) receptor and which inter alia may be used fortreating eating disorders.

[0011] EP-A-655 440 discloses 1-aminoethylindoles having activity on the5-HT_(2c) receptor and which may be used for treating eating disorders.

[0012] EP-A-572 863 discloses pyrazinoindoles having activity on the5-HT_(2c) receptor and which may be used for treating eating disorders.

[0013] J. Med. Chem. 1978, 21, 536-542 and U.S. Pat. No. 4,081,542disclose a series of piperazinylpyrazines having centralserotonin-mimetic activity.

[0014] U.S. Pat. No. 4,078,063 discloses a series ofpiperazinylpyridines having anorexic activity.

[0015] J. Med. Chem. 1981, 24, 93-101 discloses a series ofpiperazinylquinoxalines with central serotoninmimetic activity.

[0016] ES 514549 discloses piperazine derivative with anorexigenicaction.

[0017] EP 370560 discloses 1-[mono- orbis(trifluoromethyl)-2-pyridinyl]piperazines as central nervous systemagents.

[0018] WO 98/33504 discloses a new medical use of1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]piperazine, in particular toa new method of treating urinary incontinence.

[0019] WO 02/30902 discloses crystal forms of1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]piperazine hydrochloride.

[0020] EP 1213017 discloses the use of a 5-HT_(2c) receptor agonist,e.g., 1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]piperazine, for thetreatment of hot flushes.

[0021] J. Med Chem. 1987, 30, 1210-1214 discloses N,N-disubstituted6-alkoxy-2-pyridinamines as anticonvulsant agents including1-(6-methoxy-2-pyridinyl)piperazine, 1-(6-ethoxy-2-pyridinyl)piperazine,1-(6-isopropoxy-2-pyridinyl)piperazine,1-(6-isobutoxy-2-pyridinyl)piperazine,1-(6-cyclopropylmethoxy-2-pyridinyl)piperazine,1-(6-cyclohexylmethoxy-2-pyridinyl)piperazine, and1-(6-cyclohexyloxy-2-pyridinyl)piperazine.

[0022] J. Med. Chem. 1989, 32, 1237-1242 discloses6-alkyl-N,N-disubstituted-2-pyridinamines as anticonvulsant agentsincluding 1-(6-butylthio-2-pyridinyl)piperazine,1-(6-cyclohexylmethyl-2-pyridinyl)piperazine and1-[6-(2-phenylethyl)-2-pyridinyl]piperazine.

[0023] JP 07300474 discloses drugs for treatment of diseases related toserotoninergic nerve including 1-(6-phenoxy-2-pyridinyl)piperazine and1-[6-(substituted)phenoxy-2-pyridinyl]piperazines,1-(6-benzyloxy-2-pyridinyl)piperazine,1-(6-cyclobutyloxy-2-pyridinyl)piperazine, and1-(6-cyclopentyloxy-2-pyridinyl)piperazine

[0024] EP 580465 discloses heterocyclic piperazines as 5-HT₃ agonistsincluding 6-chloro-2-(3-methylpiperazinyl)pyridine and6-chloro-2-(4-methylpiperazinyl)pyridine.

[0025] WO 00/12475 discloses indoline derivatives as 5-HT_(2b) and/or5-HT_(2c) receptor ligands, especially for the treatment of obesity.

[0026] WO 00/12510 discloses pyrroloindoles, pyridoindoles andazepinoindoles as 5-HT_(2c) receptor agonists, particularly for thetreatment of obesity.

[0027] WO 00/12482 discloses indazole derivatives as selective, directlyactive 5-HT_(2c) receptor ligands, preferably 5-HT_(2c) receptoragonists, particularly for use as anti-obesity agents.

[0028] WO 00/12502 discloses pyrroloquinolines as 5-HT_(2c) receptoragonists, particularly for use as anti-obesity agents.

[0029] WO 00/35922 discloses2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)ones as 5HT_(2c)agonists, which may be used for the treatment of obesity.

[0030] WO 00/44737 discloses aminoalkylbenzofurans as 5-HT_(2c)agonists, which may be used for the treatment of obesity.

[0031] Further compounds reported to be 5HT_(2c) receptor agonists are,for example, indazolylpropylamines of the type described in WO 00/12481;indazoles of the type described in WO 00/17170; piperazinylpyrazines ofthe type described in WO 00/76984; WO 02/40456 and WO 02/40457;heterocycle fused γ-carbolines of the type described in WO 00/77001, WO00/77002 and WO 00/77010; benzofurylpiperazines of the type described inWO 01/09111 and WO 01/09123; benzofurans of the type described in WO01/09122; benzothiophenes of the type described in 01/09126;aminoalkylindazoles of the type described in WO 98/30548; indoles of thetype described in WO 01/12603; indolines of the type described in WO01/12602 and WO 02/44152; pyrazino(aza)indoles of the type described inWO 00/44753; diaza-cyclopenta[a]indenes of the type described in EP1132389; piperazine derivatives of the type described in WO 02/10169; WO02/72584 and WO 02/48124; quinoxalinones of the type described in U.S.Pat. No. 6,372,745, and tricyclic pyrroles or pyrazoles of the typedescribed in WO 98/56768.

[0032] WO 95/01976 discloses indoline derivatives active as 5-HT_(2c)antagonists and of potential use in the treatment of CNS disorders.

[0033] WO 99/58490 discloses aryl-hydronaphthalen-alkanamines which mayeffectuate partial or complete blockage of serotonergic 5-HT_(2c)receptors in an organism.

[0034] WO 03/00666 discloses [1,2′]bipyrazinyl 5-HT₂ receptor ligands,in particular 5-HT_(2c) receptor ligands, for the treatment of sexualdysfunction.

[0035] WO 03/00663 discloses piperazinylpyrimidines as 5-HT₂ receptorligands, in particular 5-HT_(2c) receptor ligands, for the treatment ofsexual disorders.

[0036] WO 02/51844 discloses cycloalkyl fused indole derivatives andtheir use as 5-HT_(2b) and 5-HT_(2c) receptor ligands.

[0037] WO 02/42304 discloses cyclopenta[b][1,4]diazepino[6,7-hi]indolesas selective 5-HT_(2c) receptor agonists.

[0038] WO 02/36596 discloses diazepinocarbazoles and related compoundsas serotonin 5-HT_(2c) agonists.

SUMMARY OF THE INVENTION

[0039] According to the invention novel compounds of the general formula(I) are provided:

[0040] wherein

[0041] R¹ is selected from H, C₁₋₄ alkyl, 2-hydroxyethyl, 2-cyanoethyl,tetrahydropyran-2-yl, and a nitrogen protecting group;

[0042] R² and R³ each, independently, represent H or CH₃;

[0043] R⁴ is selected from halogen, O—R⁵, NH—R⁵ or S—R⁵, wherein

[0044] R⁵ is selected from aryl, aryl-C₁₋₆-alkyl, aryloxy-C₂₋₆-alkyl,heteroaryl, heteroaryl-C₁₋₆-alkyl, heteroaryloxy-C₂₋₆-alkyl,C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₄-alkyl, C₁₋₆-alkyl,2-tetrahydrofuryl, 3-tetrahydrofuryl, 2-tetrahydrofurfuryl,3-tetrahydrofurfuryl, piperidine-4-yl, tetrahydropyran-4-yl,C₃₋₆-alkynyl, C₃₋₆-alkenyl, or fluoro-C₂₋₄-alkyl;

[0045] and wherein any aryl or heteroaryl residue, alone or as part ofanother group, may be unsubstituted or substituted with one or more ofC₁₋₄-alkyl, C₁₋₄-alkoxy, C₁₋₄-alkylthio, C₂₋₄-acyl, C₁₋₄-alkylsulphonyl,cyano, nitro, hydroxy, C₂₋₆-alkenyl, C₂₋₆-alkynyl, fluoromethyl,trifluoromethyl, trifluoromethoxy, halogen, —N(R⁶)(R⁷), aryl, aryloxy,arylthio, aryl-C₁₋₄-alkyl, aryl-C₂₋₄-alkenyl, aryl-C₂₋₄-alkynyl,heteroaryl, heteroaryloxy, heteroarylthio, heteroaryl-C₁₋₄-alkyl,aryl-C₁₋₄-alkoxy, aryloxy-C₁₋₄-alkyl, or dimethylamino-C₂₋₄-alkoxy,wherein

[0046] R⁶ and R⁷ are, independently of each other, hydrogen, methyl orethyl; or form a pyrrolidine, piperazine, morpholine, thiomorpholine ora piperidine ring together with the nitrogen atom to which they arebound;

[0047] and wherein any aryl or heteroaryl residue as substituents onaryl or heteroaryl, alone or as part of another group, in turn may besubstituted in one or more positions, preferably one, independently ofeach other by C₁₋₄-alkyl, C₁₋₄-alkoxy, halogen, trifluoromethyl, cyano,hydroxy or dimethylamino;

[0048] and pharmaceutically acceptable salts, hydrates, solvates,geometrical isomers, tautomers, optical isomers, N-oxides and prodrugforms thereof, with the proviso that, when R⁴ is halogen at least one ofR¹, R², or R³ is not hydrogen.

[0049] When R⁴ is halogen, it is preferred that either:

[0050] (i) R¹ is selected from C₁₋₄ alkyl, 2-hydroxyethyl, 2-cyanoethyl,tetrahydropyran-2-yl, and a nitrogen protecting group; or

[0051] (ii) R¹ is selected from H, C₁₋₄ alkyl, 2-hydroxyethyl,2-cyanoethyl, tetrahydropyran-2-yl, and a nitrogen protecting group; andat least one of R² and R³ is CH₃;

[0052] In case the compounds of formula (I) can be in the form ofoptical isomers, the invention comprises the racemic mixture as well asthe individual enantiomers as such.

[0053] In case the compounds of formula (I) contain groups, which mayexist in tautomeric forms, the invention comprises the tautomeric formsof the compounds as well as mixtures thereof.

[0054] In case the compounds of formula (I) can be in the form ofgeometrical isomers, the invention comprises the geometrical isomers aswell as mixtures thereof.

[0055] According to another aspect, the invention provides the compoundsaccording to formula (I) above for use in therapy.

[0056] Still another aspect of the invention provides a pharmaceuticalcomposition comprising a compound according to formula (I) above as theactive ingredient, preferably together with a pharmaceuticallyacceptable carrier and, if desired, other pharmacologically activeagents.

[0057] In yet another aspect, the invention provides a method for thetreatment of a human or animal subject suffering from aserotonin-related disorder or condition, particularly 5-HT_(2c)receptor-related, such as memory disorders including Alzheimer'sdisease; schizophrenia; mood disorders; anxiety disorders; pain;substance abuse; sexual dysfunction; epilepsy; glaucoma; urinaryincontinence; menopausal and post-menopausal hot flushes; type IIdiabetes; eating disorders, such as binge eating disorders, anorexianervosa and bulimia; and weight gain associated with antipsychotic drugadministration; and particularly obesity. The method includesadministering an effective amount of a compound of formula (I), or acomposition having a compound of formula (I) in it.

[0058] Another aspect of the invention relates to the use of thecompounds of formula (I) for the manufacture of a medicament for thetreatment of a serotonin-related disorder or condition, particularly5-HT_(2c) receptor-related, such as memory disorders includingAlzheimer's disease; schizophrenia; mood disorders; anxiety disorders;pain; substance abuse; sexual dysfunction; epilepsy; glaucoma; urinaryincontinence; menopausal and post-menopausal hot flushes; type IIdiabetes; eating disorders, such as binge eating disorders, anorexianervosa and bulimia; and weight gain associated with antipsychotic drugadministration; and particularly obesity. In one aspect, the manufactureof a medicament for the treatment of a serotonin-related disorder orcondition can include the step of preparing a pharmaceutical compositionhaving a compound of any of the formulae described herein and apharmaceutically acceptable carrier. A method for preparing thepharmaceutical composition can include the step of combining a compoundof any of the formulae described herein and a pharmaceuticallyacceptable carrier.

[0059] Finally a method for modulating 5HT_(2c) receptor function is anaspect of the invention.

[0060] The methods delineated herein can also include the step ofidentifying that a subject is in need of treatment of serotonin-relateddisorders or conditions, particularly 5-HT_(2c) receptor-related, in thesubject.

DETAILED DESCRIPTION OF THE INVENTION

[0061] According to the present invention, a class of novel compoundsthat bind to the 5-HT_(2c) receptor has been developed. The compoundsmay act as receptor agonists or antagonists at the 5-HT_(2c) receptorand may therefore be used for the treatment of serotonin-relateddisorders or conditions, particularly 5-HT_(2c) receptor-related.

[0062] First, the various terms used, separately and in combinations, inthe above definition of the compounds having the general formula (I)will be explained.

[0063] The expression ”C₁₋₆ alkyl” refers to straight-chained andbranched alkyl groups containing from 1 to 6 carbon atoms. ParticularC₁₋₆ alkyl groups are methyl, ethyl, n-propyl, isopropyl, tert-butyl,n-pentyl, isopentyl, n-hexyl, and isohexyl. Derived expressions such as“C₁₋₄ alkoxy” and “C₁₋₄ alkylthio” are to be constructed accordingly.

[0064] The expression “C₂₋₆ alkenyl” as used herein refers tostraight-chained and branched alkenyl groups containing from 2 to 6carbon atoms. Typical examples include vinyl, allyl, 3,3-dimethylallyl,1-butenyl, and 2-butenyl groups.

[0065] The expression “C₂₋₆ alkynyl” as used herein refers tostraight-chained and branched alkynyl groups containing from 2 to 6carbon atoms. Typical examples include ethynyl and propargyl groups.

[0066] By “heteroatom” is meant nitrogen, oxygen, sulphur, and inheterocyclic rings (including heteroaromatic as well as saturated andpartially saturated heterocyclic rings), also selenium.

[0067] The term “aryl” is intended to include aromatic rings (monocyclicor bicyclic) having from 6 to 10 ring carbon atoms, such as phenyl,1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl. Thearyl group can be linked to the remainder of the molecule via a carbonatom in any ring.

[0068] The term “heteroaryl” means a mono- or bicyclic aromatic ringsystem, only one ring need be aromatic, and which can be linked to theremainder of the molecule via a carbon or nitrogen atom in any ring, andhaving from 5 to 10 ring atoms (mono- or bicyclic), in which one or moreof the ring atoms are heteroatoms such as nitrogen, sulphur, oxygen andselenium and the remainder are carbon atoms. Examples of such heteroarylrings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole,thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine,pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman,isochroman, coumarin, quinoline, quinoxaline, isoquinoline, phthalazine,cinnoline, quinazoline, indole, isoindole, indoline, isoindoline,benzothiophene, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran,benzoxazole, 2,1,3-benzoxadiazole, benzothiazole,2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole, benzimidazole,indazole, 2,3-dihydro-1,4-benzodioxine, 1,3-benzodioxole,1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzoxazine,1,5-naphthyridine, 1,8-naphthyridine,3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine, and2,3-dihydro-1,4-benzoxathiine. If a bicyclic aryl or heteroaryl ring issubstituted, it may be substituted in any ring.

[0069] Exemplary aryl-C₁₋₆-alkyl, in which the alkyl portion of thegroup may be straight or branched, include benzyl, 2-naphthylmethyl,2-phenylethyl, 3-phenyl-1-propyl, 1-phenylethyl, 1-phenyl-2-propyl,2-phenyl-1-propyl and the like.

[0070] Exemplary aryloxy-C₂₋₆-alkyl, in which the alkyl portion of thegroup may be straight or branched, include 2-phenoxyethyl,2-(1-naphthyloxy)ethyl, 3-(2-naphthyloxy)-1-propyl, 3-phenoxy-1-propyl,4-phenoxy-1-butyl, 5-phenoxy-1-pentyl, 1-phenoxy-2-propyl and the like.

[0071] Exemplary C₃₋₆-cycloalkyl-C₁₋₄-alkyl, in which the alkyl portionof the group may be straight or branched, include cyclopropylmethyl,cyclopentylmethyl, 2-cyclohexylethyl, 1-cyclohexylethyl,1-cyclopropylethyl, 1-cyclobutylethyl and the like.

[0072] Exemplary heteroaryloxy-C₂₋₆-alkyl include2-(8-quinolinyloxy)ethyl, 2-(3-pyridinyloxy)ethyl,3-(8-quinolinyloxy)propyl and the like.

[0073] Halogen includes fluorine, chlorine, bromine or iodine,preferably fluorine, chlorine or bromine.

[0074] Where it is stated above that aryl and heteroaryl residues may besubstituted (in one or more positions), this applies to aryl andheteroaryl per se as well as to any combined groups containing aryl orheteroaryl residues, such as heteroaryloxy-C₂₋₆-alkyl, aryl-C₁₋₆-alkyletc.

[0075] The term “N-oxides” means that one or more nitrogen atoms, whenpresent in a compound, are in N-oxide form (N→O).

[0076] The term “prodrug forms” means a pharmacologically acceptablederivative, such as a carbamate or an amide, which derivative isbiotransformed in the body to form the active drug. Reference is made toGoodman and Gilman's, The Pharmacological basis of Therapeutics, 8^(th)ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”, p. 13-15.

[0077] “Pharmnaceutically acceptable” means being useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes being useful forveterinary use as well as human pharmaceutical use.

[0078] “Pharmaceutically acceptable salts” mean salts which arepharmaceutically acceptable, as defined above, and which possess thedesired pharmacological activity. Such salts include acid addition saltsformed with organic and inorganic acids, such as hydrogen chloride,hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid,acetic acid, glycolic acid, maleic acid, malonic acid, malic acid,oxalic acid, toluenesulphonic acid, methanesulphonic acid, fumaric acid,succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acidand the like.

[0079] The expression “comprising” means “including but not limited to.”Thus, other non-mentioned substances, additives or carriers may bepresent.

[0080] “A nitrogen protecting group” (i e a value for R¹) refers to agroup covalently bonded to a nitrogen atom, or any group used toderivatize nitrogen atom (e.g., the nitrogen atom in an amino group).The group may be introduced or cleaved off by conventional methods suchas those described in Protective Groups in Organic Synthesis, John Wiley& Sons, 1991. Examples of the nitrogen protecting groups include tritylor t-butoxycarbonyl and those delineated in Protective Groups in OrganicSynthesis, John Wiley & Sons, 1991 and subsequent editions thereof.

[0081] It is preferred that R¹ is hydrogen.

[0082] It is also preferred that R⁴ is selected from chlorine, O—R⁵, andS—R⁵.

[0083] It is also preferred that R⁵ is selected from aryl-C₁₋₆-alkyl,aryloxy-C₂₋₆-alkyl, heteroaryl-C₁₋₆-alkyl, heteroaryloxy-C₂₋₆-alkyl,C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₄-alkyl, C₁₋₆-alkyl,2-tetrahydrofurfuryl, and wherein any aryl or heteroaryl residue, aloneor as part of another group, may be unsubstituted or substituted withone or more of C₁₋₄-alkyl, C₁₋₄-alkoxy, cyano, halogen,aryloxy-C₁₋₄-alkyl.

[0084] It is more preferred that R⁵ is selected from benzyl,2-chlorobenzyl, 3-cyanobenzyl, 2-cyclohexylethyl, cyclopentyl,2-cyclopentylethyl, 2,3-difluorobenzyl, 2,6-difluorobenzyl,2-(2,6-difluorophenoxy)ethyl, 2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl,ethyl, 5-fluoro-2-methoxybenzyl, furan-2-ylmethyl, methyl,α-methylbenzyl, 3-methylbenzyl, 2-(naphthalene-2-yloxy)ethyl,2-phenoxyethyl, 2-phenoxymethylbenzyl, n-propyl,3-(pyridin-3-yl)-n-propyl, 2-(8-quinolinyloxy)ethyl,tetrahydrofuran-2-ylmethyl, 3-thienylmetyl.

[0085] It is also preferred that the carbon atom, to which R² isattached, is in the (S)-configuration when R² is methyl and R¹ and R³both are hydrogen.

[0086] It is also preferred that the carbon atom, to which R³ isattached, is in the (R)-configuration when R³ is methyl and R¹ and R²both are hydrogen.

[0087] Preferred compounds of the general formula (I) above are thefollowing compounds (corresponding to Examples 6-43 below):

[0088]1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-3-(S)-methyl-piperazine

[0089]1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-3-(R)-methylpiperazine

[0090]1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-2-(R)-methyl-piperazine

[0091]1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-2-(S)-methyl-piperazine,hydrochloride

[0092]1-[6-(2-Phenoxy-ethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate

[0093]1-[6-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate

[0094]1-[6-(Thiophen-3-ylmethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate

[0095]3-(6-Piperazin-1-yl-3-trifluoromethyl-pyridin-2-yloxymethyl)-benzonitrile,acetate

[0096]1-[6-(3-Methyl-benzylsulfanyl)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate

[0097]1-[6-(2-Chloro-benzylsulfanyl)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate

[0098]1-[6-(2,3-Difluoro-benzyloxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate

[0099] 1-(6-Ethylsulfanyl-5-trifluoromethyl-pyridin-2-yl)-piperazine,acetate

[0100] 1-(6-Propoxy-5-trifluoromethyl-pyridin-2-yl)-piperazine, acetate

[0101] 1-(6-Cyclopentyloxy-5-trifluoromethyl-pyrdin-2-yl)-piperazine,acetate

[0102]1-[6-(1-Phenyl-ethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate

[0103]8-[2-(6-Piperazin-1-yl-3-trifluoromethyl-pyridin-2-yloxy)-ethoxy]-quinoline,acetate

[0104]1-[6-(2,6-Difluoro-benzyloxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate

[0105]1-[6-(3-{Pyridin-3-yl}propoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate

[0106] 1-(6-Benzyloxy-5-trifluoromethyl-pyrdin-2-yl)-piperazine, acetate

[0107]1-[6-(Furan-2-ylmethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate

[0108]1-{6-[2-(2,6-Difluoro-phenoxy)-ethoxy]-5-trifluoromethyl-pyrdin-2-yl}-piperazine,acetate

[0109]1-[6-(2-Chloro-benzylsulfanyl)-5-trifluoromethyl-pyridin-2-yl]-2-(R)-methyl-piperazine,acetate

[0110]1-(6-Ethylsulfanyl-5-trifluoromethyl-pyridin-2-yl)-3-(S)-methyl-piperazine,acetate

[0111]1-(6-Ethylsulfanyl-5-trifluoromethyl-pyridin-2-yl)-3-(R)-methyl-piperazine,acetate

[0112]1-(6-Ethylsulfanyl-5-trifluoromethyl-pyridin-2-yl)-2-(R)-methyl-piperazine,acetate

[0113]1-(6-Benzyloxy-5-trifluoromethyl-pyridin-2-yl)-3-(S)-methyl-piperazine,acetate

[0114]1-(6-Benzyloxy-5-trifluoromethyl-pyridin-2-yl)-3-(R)-methyl-piperazine,acetate

[0115]1-(6-Benzyloxy-5-trifluoromethyl-pyridin-2-yl)-2-(R)-methyl-piperazine,acetate

[0116]1-(6-Benzyloxy-5-trifluoromethyl-pyridin-2-yl)-2-(S)-methyl-piperazine,acetate

[0117] 1-(6-Methoxy-5-trifluoromethyl-pyridin-2-yl)-piperazine, acetate

[0118]1-[6-(5-Fluoro-2-methoxy-benzyloxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate

[0119]1-{6-[2-(Naphthalen-2-yloxy)-ethoxy]-5-trifluoromethyl-pyridin-2-yl}-piperazine,acetate

[0120]1-[6-(2-Chloro-benzylsulfanyl)-5-trifluoromethyl-pyridin-2-yl]-3-(S)-methyl-piperazine,acetate

[0121]1-[6-(2-Chloro-benzylsulfanyl)-5-trifluoromethyl-pyridin-2-yl]-2-(S)-methyl-piperazine,acetate

[0122]1-[6-(2-Phenoxymethyl-benzyloxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate

[0123]1-[6-Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate

[0124]1-[6-(2-Cyclopentyl-ethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate

[0125]1-[6-(2-Cyclohexyl-ethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate and their pharmacologically acceptable salts and solvates.

[0126] The compounds corresponding to Examples 6, 8, 10-38, and 41-43are even more preferred.

[0127] As mentioned above, the compounds of the present invention areuseful for the treatment, including prophylactic treatment, ofserotonin-related, especially 5-HT_(2c) receptor-related, disorders andconditions, in a human being or in an animal, including e.g. pets, suchas memory disorders including Alzheimer's disease; schizophrenia; mooddisorders, including, but not restricted to, major depression andbipolar depression, including both mild and manic bipolar disorder,seasonal affective disorder (SAD); anxiety disorders, includingsituational anxiety, generalized anxiety disorder, primary anxietydisorders (panic disorders, phobias, obsessive-compulsive disorders, andpost-traumatic stress disorders), and secondary anxiety disorders (forexample anxiety associated with substance abuse); pain; substance abuse;sexual dysfunction; epilepsy; glaucoma; urinary incontinence; menopausaland post-menopausal hot flushes; type II diabetes; eating disorders,such as binge eating disorders, anorexia nervosa and bulimia; weightgain associated with antipsychotic drug administration; and particularlyobesity.

[0128] The compounds of the present invention in radiolabelled form, maybe used as a diagnostic agent.

[0129] Processes for Preparation

[0130] This invention also relates to methods of making compounds of anyformulae delineated herein comprising reacting any one or more of thecompounds or formulae delineated herein including any processesdelineated herein.

[0131] In one aspect, the invention is a method of making a compound offormula (I) delineated herein. The compounds of general formula (I)above may be prepared by, or in analogy with, conventional methods, andespecially according to or in analogy with the following method.

[0132] Compounds of formula (I) above in which R⁴ is halogen, O—R⁵,NH—R⁵ or S—R⁵ are prepared by reacting a compound of the structuralformula (II):

[0133] wherein Hal is halogen; with 1 to 10 molar equivalents of anappropriate piperazine derivative of formula (III):

[0134] wherein R¹, R², and R³ are as defined above; in a solvent such asdimethylsulfoxide (DMSO), acetonitrile, dioxane, tetrahydrofuran (THF),n-butanol, N,N-dimethylformamide (DMF), or in a mixture of solvents suchas DMF/dioxane, optionally in the presence of a base, such as K₂CO₃,Na₂CO₃, Cs₂CO₃, NaOH, triethylamine, pyridine or the like, at 0-200° C.for 1-24 hours to produce a compound of formula (IV):

[0135] wherein R¹, R², and R³ are as defined above and Hal is halogen.

[0136] The compound of formula (IV) is reacted with an appropriatealcohol, amine, or thiol as defined by O—R⁵, NH—R⁵ or S—R⁵ above, or itscorresponding anions to produce a compound of the formula (I) above. Theappropriate alcohol, amine, or thiol may be converted completely orpartially to its corresponding anion by treatment with bases, such astriethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, K₂CO₃, NaOH, NaH,KO-t-Bu, lithium diisopropylamide or the like. The reaction is carriedout in a solvent, such as DMSO, dioxane, THF, tert-butanol or DMF, at0-200° C. for 1-24 hours.

[0137] An obtained compound of formula (I) above may be converted toanother compound of formula (I) by methods well known in the art.

[0138] The chemicals used in the above-described synthetic routes mayinclude, for example, solvents, reagents, catalysts, protecting groupand deprotecting group reagents. The methods described above may alsoadditionally include steps, either before or after the steps describedspecifically herein, to add or remove suitable protecting groups inorder to ultimately allow synthesis of the compounds of formula (I).When R¹ is a nitrogen protecting group as defined above, the subsequentN-deprotection is carried out by conventional methods. In addition,various synthetic steps may be performed in an alternate sequence ororder to give the desired compounds. Synthetic chemistry transformationsand protecting group methodologies (protection and deprotection) usefulin synthesizing applicable compounds are known in the art and include,for example, those described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2^(nd) Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995); and subsequent editions thereof.

[0139] The process that is described above may be carried out to give acompound of the invention in the form of a free base or as an acidaddition salt. A pharmaceutically acceptable acid addition salt may beobtained by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.Examples of addition salt forming acids are maleic acid, fumaric acid,succinic acid, methanesulfonic acid, acetic acid, malic acid, oxalicacid, benzoic acid, hydrochloric acid, sulphuric acid, phosphoric acid,and the like.

[0140] The compounds of formula (I) may possess one or more chiralcarbon atoms, and they may therefore be obtained in the form of opticalisomers, e.g. as a pure enantiomer, or as a mixture of enantiomers(racemate) or as a mixture containing diastereomers. The separation ofmixtures of optical isomers to obtain pure enantiomers is well known inthe art and may, for example, be achieved by fractional crystallizationof salts with optically active (chiral) acids or by chromatographicseparation on chiral columns.

[0141] The necessary starting materials for preparing the compounds offormula (I) are either known or may be prepared in analogy with thepreparation of known compounds.

[0142] In accordance with the present invention, the compounds offormula (I), in the form of free bases or salts with physiologicallyacceptable acids, can be brought into suitable galenic forms, such ascompositions for oral use, for injection, for nasal spray administrationor the like, in accordance with accepted pharmaceutical procedures. Suchpharmaceutical compositions according to the invention comprise aneffective amount of the compounds of formula (I) in association withcompatible pharmaceutically acceptable carrier materials, or diluents,as are well known in the art. The carriers may be any inert material,organic or inorganic, suitable for enteral, percutaneous, subcutaneousor parenteral administration, such as: water, gelatin, gum arabicum,lactose, microcrystalline cellulose, starch, sodium starch glycolate,calcium hydrogen phosphate, magnesium stearate, talcum, colloidalsilicon dioxide, and the like. Such compositions may also contain otherpharmacologically active agents, and conventional additives, such asstabilizers, wetting agents, emulsifiers, flavoring agents, buffers, andthe like.

[0143] The compositions according to the invention can e.g. be made upin solid or liquid form for oral administration, such as tablets, pills,capsules, powders, syrups, elixirs, dispersible granules, cachets,suppositories and the like, in the form of sterile solutions,suspensions or emulsions for parenteral administration, sprays, e.g. anasal spray, transdermal preparations, e.g. patches, and the like.

[0144] As mentioned above, the compounds of the invention may be usedfor the treatment of serotonin-related, especially 5-HT_(2c)receptor-related disorders and conditions in a human being or an animal,such as memory disorders including Alzheimer's disease; schizophrenia;mood disorders; anxiety disorders; pain; substance abuse; sexualdysfunction; epilepsy; glaucoma; urinary incontinence; menopausal andpost-menopausal hot flushes; type II diabetes; eating disorders, such asbinge eating disorders, anorexia nervosa and bulimia; weight gainassociated with antipsychotic drug administration; and particularlyobesity.

[0145] Also within the scope of this invention is a method formodulating (e.g., inhibiting or stimulating) 5-HT_(2c)-receptoractivity. The method includes administering to a subject in need thereofan effective amount of a compound of the formula (I).

[0146] The methods delineated herein can also include the step ofidentifying that a subject is in need of treatment of serotonin-related,especially 5-HT_(2c) receptor-related, disorders and conditions in thesubject (e.g., a mammal, a human being, a horse, a dog, or a cat).

[0147] “An effective amount” refers to an amount of a compound, whichconfers a therapeutic effect on the treated subject. The therapeuticeffect may be objective (i.e., measurable by some test or marker) orsubjective (i.e., subject gives an indication of or feels an effect).For clinical use, the compounds of the invention are formulated intopharmaceutical formulations for oral, rectal, parenteral or other modeof administration. Usually the amount of active compounds is between0.1-95% by weight of the preparation, preferably between 0.2-20% byweight in preparations for parenteral use and preferably between 1 and50% by weight in preparations for oral administration.

[0148] The dose level and frequency of dosage of the specific compoundwill vary depending on a variety of factors including the potency of thespecific compound employed, the metabolic stability and length of actionof that compound, the patient's age, body weight, general health, sex,diet, mode and time of administration, rate of excretion, drugcombination, the severity of the condition to be treated, and thepatient undergoing therapy. The daily dosage may, for example, rangefrom about 0.001 mg to about 100 mg per kilo of body weight,administered singly or multiply in doses, e.g. from about 0.01 mg toabout 25 mg each. Normally, such a dosage is given orally but parenteraladministration may also be chosen.

[0149] All references cited herein, whether in print, electronic,computer readable storage media or other form, are expresslyincorporated by reference in their entirety, including but not limitedto, abstracts, articles, journals, publications, texts, treatises,internet web sites, databases, patents, and patent publications.

[0150] The invention will now be illustrated with the followingexamples, which however, are for illustrative purposes are not intendedto limit the scope of the invention.

EXAMPLES

[0151] Experimental Methods

[0152] The ¹H-and ¹³C-NMR-spectra were obtained with a Bruker DPX 400.The DPFGSE-NOE experiments were obtained with a Varian INOVA 400. Themixing time was 0.8 seconds. The preparative LC was performed on apreparative LC-MS Gilson-Finnigan with a 50×20 mm S 5 μm, 120A column.The flow was 30 mL/min and different gradients of 0.1% acetic acid inwater and acetonitrile were used. The accurate masses were determinedwith a Micromass LCT with electrospray ionization. The elementalanalyses were performed with a Vario EL instrument. A Koefler bench wasused to measure the melting points, which are not corrected.

Examples 1-5

[0153] Preparation of Intermediates.

General Procedure for Examples 1-2

[0154] To a suspension of LiAlH₄ (1.2 g, 32 mmol) in dry THF (5 mL) wasadded the aldehyde or carboxylic acid (10 mmol) and the mixtures werestirred at room temperature for two hours. Mixtures with aldehydes asstarting materials were put aside and the acids were heated at 60° C.overnight. To each mixture was added in consecutive order water (1.2mL), 2 M aqueous NaOH (1.2 mL), and water (3.6 mL). The precipitate wasfiltered off and the solvent was removed under reduced pressure to yieldthe target products as oils.

Example 1

[0155] (5-Fluoro-2-methoxy-phenyl)-methanol.

[0156] The title compound was prepared starting from5-fluoro-2-methoxybenzaldehyde and was obtained as a light red oil (94%yield). Fragmenting MS analysis supports the stated structure. Purity97% (GC). ¹H NMR (CDCl₃) δ3.28 (s, 3 H), 4.64 (s, 2 H), 6.78 (m, 1 H),6.93 (m, 1 H), 7.02 (m, 1 H). ¹³C NMR (CDCl₃) δ55.73, 61.34, 110.83 (d,J=8.5 Hz), 114.22 (d, J=22.6Hz), 115.26 (d, J=23.3 Hz), 138.68 (d, J=6.4Hz), 153.18 (d, J=2.1 Hz), 156.95 (d, J=238.8 Hz).

Example 2

[0157] (2-Phenoxymethyl-phenyl)-methanol.

[0158] The title compound was prepared starting from2-(phenoxymethyl)benzoic acid and was obtained as a light yellow oil(96% yield). Fragmenting MS analysis supports the stated structure.Purity 94% (GC). Previously reported in J. Chem. Soc., 1954, 2819-2826.

Example 3

[0159] 3-(S)-Methyl-1-trityl-piperazine.

[0160] To a solution of 2-(S)-methylpiperazine (3.79 g, 37.9 mmol) inCHCl₃ (100 mL) was trityl chloride (10.56 g, 37.9 mmol) added in oneportion. The exothermic reaction was stirred at ambient temperature fortwo hours, the organic phase was washed three times with water, dried(MgSO₄) and the solvent was evaporated at reduced pressure to give 12.5g (96%) of a colorless foam that solidified to a crisp over night. ¹HNMR (CDCl₃) δ1.06 (d, J=5.5 Hz, 3 H), 1.35 (m, 1 H), 1.61 (m, 1 H), 3.01(m, 3 H), 3.14 (m, 1 H), 3.31 (m, 1 H), 7.08 (m, 3 H), 7.16 (m, 6 H),7.35 (m, 6 H). ¹³C NMR (CDCl₃) δ18.17, 44.46, 46.68, 51.59, 54.03,126.26, 127.13, 127.68, 129.07 br. The racemate of the title compound isreported in Bioorg. Med. Chem. Lett. 2000, 10, 2643-2646.

Example 4

[0161] 3-(R)-Methyl-1-trityl-piperazine.

[0162] The title compound was prepared as described in WO 00/76984starting from 2-(R)-methylpiperazine (5.51 g, 55.1 mmol). This gave 18.8g (99%) of a white crisp. HRMS m/z calcd for C₂₄H₂₆N₂ (M)⁺ 342.2096,found 342.2110.

Example 5

[0163] 1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-piperazine.

[0164] Step 1:4-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acidtert-butyl ester.

[0165] To a suspension of tert-butyl-1-piperazine carboxylate (27.0 g,145 mmol) and K₂CO₃ (40.0 g, 290 mmol) in DMSO (200 mL) were2,6-dichloro-3-trifluoromethylpyridine (29.1 g, 135 mmol) and toluene(50 mL) added. The thick slurry was stirred at 80° C. for two hours,followed by addition of toluene (0.5 L) and water (1 L). The phases wereseparated and the organic phase was washed twice with water. The solventfrom the dried (MgSO₄) organic phase was evaporated at reduced pressure.The solid residue was recrystallized from EtOAc/heptane to give whitecrystals (37 g). The filtrate from the recrystallization wasconcentrated and the residue chromatographed on a column of silica withhexane/EtOAc (90:10) to give further 6.0 g of product (total yield 85%).Purity 99% (HPLC); mp 125° C. Anal. (C₁₅H₁₉ClF₃N₃O₂) C, H, N.

[0166] Step 2: 1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-piperazine.*

[0167] The title compound was prepared from the product of Step 1 aboveusing the N-deprotection procedure given in Example 6, Step 2. Thisfurnished 29.7 g (100%) of a light yellow oil that crystallized uponstanding. A NOE between the methylene protons at C-2 in the piperazinering and the C3-hydrogen in the pyridine ring was observed. Purity 99%(HPLC); mp 56° C. Fragmenting MS analysis supports the stated structure.HRMS m/z calcd for C₁₀H₁₁ClF₃N₃ (M)⁺ 265.0594, found 265.0597.*Previously reported in EP 370560.

Example 6

[0168]1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-3-(S)-methyl-piperazine.

[0169] Step 1:4-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-2-(S)-methyl-piperazine-1-carboxylicacid tert-butyl ester.

[0170] To a suspension of 2-(S)-methylpiperazine (2.65 g, 26.5 mmol) andK₂CO₃ (4.0 g, 29 mmol) in dry DMSO (50 mL) was slowly added2,6-dichloro-3-trifluoromethylpyridine (5.70 g, 26.4 mmol). The reactionmixture was stirred at room temperature over night, filtered, dilutedwith water (ca 1 L) and extracted twice with EtOAc (100 mL). The solventfrom the combined dried (MgSO₄) organic phases was evaporated at reducedpressure to give a yellow oil (7.4 g). This material was dissolved inMeOH (100 mL), BOC anhydride (6.0 g, 27.5 mmol) was added in one portionand the reaction mixture was stirred at room temperature for two hours.Excess BOC anhydride was quenched with pyridine (3 mL) and the mixturewas left at room temperature over night. The solvent was removed atreduced pressure and the resulting oil was chromatographed on a columnof silica (60×110 mm) with hexane/EtOAc (95:5, 1 L, followed by 90:10, 1L and 80:20). Evaporation at reduced pressure of the pure fractionsyielded a colorless oil (8.05 g, 80%) that solidified to a white solidover night. Purity 97% (HPLC); mp 86° C. Fragmenting MS analysissupports the stated structure. HRMS m/z calcd for C₁₆H₂₁ClF₃N₃O₂ (M)⁺379.1274, found 379.1286.

[0171] Step 2:

[0172]1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-3-(S)-methyl-piperazine.

[0173] A solution of4-(6-chloro-5-trifluoromethyl-pyridin-2-yl)-2-(S)-methyl-piperazine-1-carboxylicacid tert-butyl ester (7.80 g, 26.4 mmol) was dissolved in CH₂Cl₂/TFA(50:50; 30 mL) and stirred at room temperature over night. The solventwas removed at reduced pressure and the resulting oil was taken upbetween alkaline water (NaOH) and CHCl₃. The aqueous phase was extractedonce with CHCl₃, the combined organic phases were dried (MgSO₄) and thesolvent was evaporated at reduced pressure to yield 5.79 g (78%) of alight yellow oil. A NOE between the methylene protons at C-2 in thepiperazine ring and the C3-hydrogen in the pyridine ring was observed.Purity 100% (HPLC). Fragmenting MS analysis supports the statedstructure. HRMS m/z calcd for C₁₁H₁₃ClF₃N₃ (M)⁺ 279.0750, found 279.0751

Example 7

[0174]1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-3-(R)-methylpiperazine.

[0175] Step 1:4-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-2-(R)-methyl-piperazine-1-carboxylicacid tert-butyl ester.

[0176] The title compound was prepared starting from2-(R)-methylpiperazine using the procedure given in Example 6, Step 1,for the (S)-isomer and was obtained as a white crystalline solid. Yield7.4 g (70%). Purity 99% (HPLC); mp 86° C. Fragmenting MS analysissupports the stated structure. HRMS m/z calcd for C₁₆H₂₁ClF₃N₃O₂ (M)⁺379.1274, found 379.1269.

[0177] Step 2:1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-3-(R)-methylpiperazine.

[0178] The title compound was prepared starting from the product of Step1 above using the N-deprotection procedure given in Example 6, Step 2,and was obtained as a light yellow oil. Yield 4.76 g (90%). Purity 99%(HPLC). Fragmenting MS analysis supports the stated structure. HRMS m/zcalcd for C₁₁H₁₃ClF₃N₃ (M)⁺ 279.0750, found 279.0742.

Example 8

[0179]1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-2-(R)-methyl-piperazine.

[0180] Step 1:1-(6-Chloro-5-trifuoromethyl-pyridin-2-yl)-2-(R)-methyl-4-trityl-piperazine.

[0181] A suspension of 3-(R)-methyl-1-trityl-piperazine (from Example 4;7.80 g, 22.9 mmol), 2,6-dichloro-3-trifluoromethylpyridine (4.50 g, 20.8mmol) and K₂CO₃ (4.0 g, 29 mmol) in DMSO (100 mL) was stirred at 80° C.over night. A mixture of EtOAc/toluene (50:50; 500 mL) was added to thefiltered solution and the mixture were washed three times with water (1L). The dried (MgSO₄) organic phase was concentrated under reducedpressure and the resulting brown oil was dissolved in heptane/EtOAc(90:10) and filtered through a plug (60×60 mm) of silica. Slowevaporation of about two thirds of the solvent at reduced pressureafforded light yellow crystals (6.11 g, 56%). Purity 100% (HPLC); mp209° C. Fragmenting MS analysis supports the stated structure. Anal.(C₃₀H₂₇ClF₃N₃) C, H, N.

[0182] Step 2:1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-2-(R)-methyl-piperazine.

[0183] A suspension of1-(6-chloro-5-trifluoromethyl-pyridin-2-yl)-2-(R)-methyl-4-trityl-piperazine(from Step 1 above; 5.70 g, 10.9 mmol) in EtOH (70 mL) was heated to 80°C. Aqueous HCl (4 M; 6 mL) was added and the mixture was heated in anopen vessel for one hour. To the clear solution was water added (100 mL)and the precipitate was filtered off. The solvent from the filtrate wasevaporated down to about 10 mL, the crystals were filtered off and theevaporation continued down to 3 mL and another portion of slightlypinkish crystals were filtered off. The combined crystal fractions weretaken up between alkaline water (NaOH)/CHCl₃. The aqueous phase waswashed twice with CHCl₃ and the combined, dried (MgSO₄), organic phaseswere evaporated at reduced pressure to give a light yellow oil (1.75 g,69%). A NOE between the methylene protons at C-2 in the piperazine ringand the C3-hydrogen in the pyridine ring was observed. Purity 99%(HPLC). Fragmenting MS analysis supports the stated structure. HRMS m/zcalcd for C₁₁H₁₃ClF₃N₃ (M)⁺ 279.0750, found 279.0744.

Example 9

[0184]1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-2-(S)-methyl-piperazine,Hydrochloride.

[0185] Step 1:

[0186]1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-2-(S)-methyl-4-trityl-piperazine.

[0187] The title compound was prepared starting from3-(S)-methyl-1-trityl-piperazine (obtained in Example 3) using theprocedure given in Example 8 for the (R)-isomer. Light yellow crystals;yield 5.1 g (43%). Purity 96% (HPLC); mp 210° C. Fragmenting MS analysissupports the stated structure. Anal. (C₃₀H₂₇ClF₃N₃) C, H, N.

[0188] Step 2:1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-2-(S)-methyl-piperazine,Hydrochloride.

[0189] The title compound was prepared starting from the product of Step1 above using the N-detritylation procedure given in Example 8, Step 2,for the (R)-isomer. This produced 2.06 g (68%) of the free base of thetitle compound obtained as a pinkish oil. The free base was convertedinto its hydrochloride salt. Purity 99% (HPLC). Fragmenting MS analysissupports the stated structure. HRMS m/z calcd for C₁₁H₁₃ClF₃N₃ (M)⁺279.0750, found 279.0738.

Examples 10-43

[0190] General Procedure

[0191] Volumes are expressed as total volumes.

[0192] To a 16 mm test tube was added;

[0193] 0.5 mmol of the appropriate alcohol or thiol

[0194] 0.4 mmol of the appropriate 6-chloro5-trifluoromethyl-2-piperazinylpyridine in DMSO (0.5 mL)

[0195] 0.65 mmol of K-t-BuO in DMSO (1.0 mL)

[0196] The reactions were stirred at room temperature for two hoursfollowed by addition of HOAc (1.25 mmol, 75 μL). The solvent wasevaporated at reduced pressure over night (Speed Vac). The remainingsolids were dissolved in water/acetonitrile/HOAc, filtered, and theproducts were purified with preparative HPLC.

[0197] Mass detection was obtained by a Micro Mass LCP with electrospraypositive ionization mode. The analytical HPLC-chromatograms wereperformed on a Hewlett Packard 1100 with a 50×4.6 mm Grom-SIL 100 ODS 0AB, 3 μm column and a 50×4.6 mm YMC-AQ 5 μm column. Different gradientsof 0.1% TFA in water and acetonitrile were used and the peaks weredetected at 254 nm. The area % under the largest peak was reported asthe purity.

[0198] Chart 1.

[0199] Starting 6-chloropyridines used in Examples 10-43.

[0200] Starting alcohols and thiols used in Examples 10-43.

Example 10

[0201]1-[6-(2-Phenoxy-ethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.

[0202] Starting materials A and 1, see Chart 1. Purity 99% (HPLC). MSm/z 368 (M+H)⁺. HRMS m/z calcd for C₁₈H₂₀F₃N₃O₂ (M)⁺ 367.1508, found367.1508.

Example 11

[0203]1-[6-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.

[0204] Starting materials A and 2, see Chart 1. Purity 94% (HPLC). MSm/z 396 (M+H)⁺. HRMS m/z calcd for C₁₉H₂₀F₃N₃O₃ (M)⁺ 395.1457, found395.1468.

Example 12

[0205]1-[6-(Thiophen-3-ylmethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.

[0206] Starting materials A and 3, see Chart 1. Purity 98% (HPLC). MSm/z 344 (M+H)⁺. HRMS m/z calcd for C₁₅H₁₆F₃N₃OS (M)⁺ 343.0966, found343.0971.

Example 13

[0207]3-(6-Piperazin-1-yl-3-trifluoromethyl-pyridin-2-yloxymethyl)-benzonitrile,acetate.

[0208] Starting materials A and 4, see Chart 1. Purity 95% (HPLC). MSm/z 363 (M+H)⁺. HRMS m/z calcd for C₁₈H₁₇F₃N₄O (M)⁺ 362.1354, found362.1365.

Example 14

[0209]1-[6-(3-Methyl-benzylsulfanyl)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.

[0210] Starting materials A and 5, see Chart 1. Purity 96% (HPLC). MSm/z 368 (M+H)⁺. HRMS m/z calcd for C₁₈H₂₀F₃N₃S (M)⁺ 367.1330, found367.1322.

Example 15

[0211]1-[6-(2-Chloro-benzylsulfanyl)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.

[0212] Starting materials A and 6, see Chart 1. Purity 98% (HPLC). MSm/z 388 (M+H)⁺. HRMS m/z calcd for C₁₇H₁₇ClF₃N₃S (M)⁺ 387.0784, found387.0773.

Example 16

[0213]1-[6-(2,3-Difluoro-benzyloxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.

[0214] Starting materials A and 7, see Chart 1. Purity 100% (HPLC). MSm/z 374 (M+H)⁺.

Example 17

[0215] 1-(6-Ethylsulfanyl-5-trifluoromethyl-pyridin-2-yl)-piperazine,acetate.

[0216] Starting materials A and 8, see Chart 1. Purity 96% (HPLC). MSm/z 292 (M+H)⁺. HRMS m/z calcd for C₁₂H₁₆F₃N₃S (M)⁺ 291.1017, found291.1018.

Example 18

[0217] 1-(6-Propoxy-5-trifluoromethyl-pyridin-2-yl)-piperazine, acetate.

[0218] Starting materials A and 9, see page Chart 1. Purity 100% (HPLC).MS m/z 290 (M+H)⁺.

Example 19

[0219] 1-(6-Cyclopentyloxy-5-trifluoromethyl-pyridin-2-yl)-piperazine,acetate.

[0220] Starting materials A and 10, see Chart 1. Purity 100% (HPLC). MSm/z 316 (M+H)⁺. HRMS m/z calcd for C₁₅H₂₀F₃N₃O (M)⁺ 315.1558, found315.1551.

Example 20

[0221]1-[6-(1-Phenyl-ethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.

[0222] Starting materials A and 11, see Chart 1. Purity 100% (HPLC). MSm/z 352 (M+H)⁺. HRMS m/z calcd for C₁₈H₂₀F₃N₃O (M)⁺ 351.1558, found351.1573.

Example 21

[0223]8-[2-(6-Piperazin-1-yl-3-trifluoromethyl-pyridin-2-yloxy)-ethoxyl-quinoline,acetate.

[0224] Starting material A and 12*, see page Chart 1. Purity 98% (HPLC).MS m/z 419 (M+H)⁺. HRMS m/z calcd for C₂₁H₂₁F₃N₄O₂ (M)⁺ 418.1617, found418.1625.

Example 22

[0225]1-[6-(2,6-Difluoro-benzyloxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.

[0226] Starting material A and 13, see Chart 1. Purity 96% (HPLC). MSm/z 374 (M+H)⁺. HRMS m/z calcd for C₁₇H₁₆F₅N₃O (M)⁺ 373.1214, found373.1209.

Example 23

[0227]1-[6-(3-{Pyridin-3-yl}propoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.

[0228] Starting material A and 14, see Chart 1. Purity 99% (HPLC). MSm/z 367 (M+H)⁺. HRMS m/z calcd for C₁₈H₂₁F₃N₄O (M)⁺ 366.1667, found366.1677.

Example 24

[0229] 1-(6-Benzyloxy-5-trifluoromethyl-pyridin-2-yl)-piperazine,acetate.

[0230] Starting material A and 15, see Chart 1. Purity 99% (HPLC). MSm/z 338 (M+H)⁺. HRMS m/z calcd for C₁₇H₁₈F₃N₃O (M)⁺ 337.1402, found337.1408.

Example 25

[0231]1-[6-(Furan-2-ylmethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.

[0232] Starting material A and 16, see Chart 1. Purity 96% (HPLC). MSm/z 328 (M+H)⁺. HRMS m/z calcd for C₁₅H₁₆F₃N₃O₂ (M)⁺ 327.1195, found327.1195.

Example 26

[0233]1-{6-2-(2,6-Difluoro-phenoxy)-ethoxy]-5-trifluoromethyl-pyridin-2-yl}-piperazine,acetate.

[0234] Starting materials A and 17*, see Chart 1. Purity 98% (HPLC). MSm/z 404 (M+H)⁺. HRMS m/z calcd for C₁₈H₁₈F₅N₃O₂ (M)⁺ 403.1319, found403.1326.

Example 27

[0235]1-[6-(2-Chloro-benzylsulfanyl)-5-trifluoromethyl-pyridin-2-yl]-2-(R)-methyl-piperazine,acetate.

[0236] Starting materials D and 6, see Chart 1. Purity 96% (HPLC). MSm/z 402 (M+H)⁺. HRMS m/z calcd for C₁₈H₁₉ClF₃N₃S (M)⁺ 401.0940, found401.0926.

Example 28

[0237]1-(6-Ethylsulfanyl-5-trifluoromethyl-pyridin-2-yl)-3-(S)-methyl-piperazine,acetate.

[0238] Starting materials B and 8, see Chart 1. Purity 100% (HPLC). MSm/z 306 (M+H)⁺. HRMS m/z calcd for C₁₃H₁₈F₃N₃S (M)⁺ 305.1174, found305.1163.

Example 29

[0239]1-(6-Ethylsulfanyl-5-trifuoromethyl-pyridin-2-yl)-3-(R)-methyl-piperazine,acetate.

[0240] Starting materials C and 8, see Chart 1. Purity 95% (HPLC). MSm/z 306 (M+H)⁺. HRMS m/z calcd for C₁₃H₁₈F₃N₃S (M)⁺ 305.1174, found305.1168.

Example 30

[0241]1-(6-Ethylsulfanyl-5-trifluoromethyl-pyridin-2-yl)-2-(R)-methyl-piperazine,acetate.

[0242] Starting materials D and 8, see Chart 1. Purity 100% (HPLC). MSm/z 306 (M+H)⁺.

[0243] HRMS m/z calcd for C₁₃H₁₈F₃N₃S (M)⁺ 305.1174, found 305.1160.

Example 31

[0244]1-(6-Benzyloxy-5-trifluoromethyl-pyridin-2-yl)-3-(S)-methyl-piperazine,acetate.

[0245] Starting materials B and 15, see Chart 1. Purity 100% (HPLC). MSml/z 352 (M+H)⁺. HRMS m/z calcd for C₁₈H₂₀F₃N₃O (M)⁺ 351.1558, found351.1553.

Example 32

[0246]1-(6-Benzyloxy-5-trifluoromethyl-pyridin-2-yl)-3-(R)-methyl-piperazine,acetate.

[0247] Starting materials C and 15, see Chart 1. Purity 99% (HPLC). MSm/z 352 (M+H)⁺. HRMS m/z calcd for C₁₈H₂₀F₃N₃O (M)⁺ 351.1558, found351.1541.

Example 33

[0248]1-(6-Benzyloxy-5-trifluoromethyl-pyridin-2-yl)-2-(R)-methyl-piperazine,acetate.

[0249] Starting materials D and 15, see Chart 1. Purity 99% (HPLC). MSm/z 352 (M+H)⁺. HRMS m/z calcd for C₁₈H₂₀F₃N₃O (M)⁺ 351.1558, found351.1551.

Example 34

[0250]1-(6-Benzyloxy-5-trifluoromethyl-pyridin-2-yl)-2-(S)-methyl-piperazine,acetate.

[0251] Starting materials E and 15, see Chart 1. Purity 100% (HPLC). MSm/z 352 (M+H)⁺. HRMS m/z calcd for C₁₈H₂₀F₃N₃O (M)⁺ 351.1558, found351.1552.

Example 35

[0252] 1-(6-Methoxy-5-trifluoromethyl-pyridin-2-yl)-piperazine, acetate.

[0253] Starting materials A and 18, see Chart 1. Purity 100% (HPLC). MSm/z 262 (M+H)⁺. HRMS m/z calcd for C₁₁H₁₄F₃N₃O (M)⁺ 261.1089, found261.1100.

Example 36

[0254]1-[6-(5-Fluoro-2-methoxy-benzyloxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.

[0255] Starting materials A and 19, see Chart 1. Purity 96% (HPLC). MSm/z 386 (M+H)⁺. HRMS m/z calcd for C₁₈H₁₉F₄N₃O₂ (M)⁺ 385.1413, found385.1408.

Example 37

[0256]1-{6-[2-(Naphthalen-2-yloxy)-ethoxyl-5-trifluoromethyl-pyridin-2-yl}-piperazine,acetate.

[0257] Starting materials A and 20, see Chart 1. Purity 100% (HPLC). MSm/z 418 (M+H)⁺. HRMS m/z calcd for C₂₂H₂₂F₃N₃O₂ (M)⁺ 417.1664, found417.1658.

Example 38

[0258]1-[6-(2-Chloro-benzylsulfanyl)-5-trifluoromethyl-pyridin-2-yl]-3-(S)-methyl-piperazine,acetate.

[0259] Starting materials B and 6, see Chart 1. Purity 100% (HPLC). MSm/z 402 (M+H)⁺. HRMS m/z calcd for C₁₈H₁₉ClF₃N₃S (M)⁺ 401.0940, found401.0950.

Example 39

[0260]1-[6-(2-Chloro-benzylsulfanyl)-5-trifluoromethyl-pyridin-2-yl]-2-(S)-methyl-piperazine,acetate.

[0261] Starting materials E and 6, see Chart 1. Purity 99% (HPLC). MSm/z 402 (M+H)⁺. HRMS m/z calcd for C₁₈H₁₉F₃N₃S (M)⁺ 401.0940, found401.0942.

Example 40

[0262]1-[6-(2-Phenoxymethyl-benzyloxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.

[0263] Starting materials A and 21, see Chart 1. Purity 100% (HPLC). MSm/z 444 (M+H)⁺. HRMS m/z calcd for C₂₄H₂₄F₃N₃O₂ (M)⁺ 443.1821, found443.1841.

Example 41

[0264]1-[6-Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.

[0265] Starting materials A and 22, see Chart 1. Purity 97% (HPLC). MSm/z 332 (M+H)⁺. HRMS m/z calcd for C₁₅H₂₀F₃N₃O₂ (M)⁺ 331.1508, found331.1504.

Example 42

[0266]1-[6-(2-Cyclopentyl-ethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.

[0267] Starting materials A and 23, see Chart 1. Purity 100% (HPLC). MSm/z 344 (M+H)⁺.

Example 43

[0268]1-[6-(2-Cyclohexyl-ethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.

[0269] Starting materials A and 24, see Chart 1. Purity 90% (HPLC). MSm/z 358 (M+H)⁺. HRMS m/z calcd for C₁₈H₂₆F₃N₃O (M)⁺ 357.2028, found357.2040.

[0270] Preparation of a Pharmaceutical Composition

Example

[0271] Preparation of Tablets Ingredients mg/tablet 1. Active compoundof formula (I) 10.0 2. Cellulose, microcrystalline 57.0 3. Calciumhydrogen phosphate 15.0 4. Sodium starch glycolate 5.0 5. Silicondioxide, colloidal 0.25 6. Magnesium stearate 0.75

[0272] The active ingredient 1 is mixed with ingredients 2, 3, 4 and 5for about 10 minutes. The magnesium stearate is then added, and theresultant mixture is mixed for about 5 minutes and compressed intotablet form with or without film-coating.

[0273] Pharmacological Methods

[0274] The ability of a compound of the invention to bind or act atspecific 5-HT receptor subtypes can be determined using in vitro and invivo assays known in the art. The biological activity of compoundsprepared in the Examples was tested using different tests.

[0275] Affinity Assay

[0276] The 5-HT_(2c) receptor affinity of compounds in the Examples wasdetermined in competition experiments, where the ability of eachcompound in serial dilution to displace ³H-labelledlabeled 5-HT, boundto membranes prepared from a transfected HEK293 cell line stablyexpressing the human 5-HT_(2c) receptor protein, was monitored byScintillation Proximity Assay technology. Non-specific binding wasdefined using 5 μM mianserin. Results obtained for exemplary compoundsof the invention are illustrated in Table 1 below. The 5-HT_(2c)receptor affinity values, expressed as percent inhibition of binding ofthe radioligand at 50 nM of test compound, were in the range of 10%-95%.The K_(i) values for the compounds towards the 5-HT_(2c) receptor werein the range 0.5-5000 nM. TABLE 1 5-HT_(2C) receptor Affinity CompoundK_(i) (nM) Example 15 1 Example 17 15 Example 21 246 Example 25 14Example 30 24 Example 36 5 Example 38 6

[0277] Efficacy Assay

[0278] The agonist efficacy at the 5-HT_(2c) receptor of the compoundsin the Examples was determined by the ability of each compound tomobilise intracellular calcium in transfected HEK293 cells, stablyexpressing the human 5-HT_(2c) receptor protein, using thecalcium-chelating fluorescent dye FLUO-3 (Sigma, St. Louis, Mo.,U.S.A.).

[0279] The maximum responses of the compounds in the Examples were inthe range of 0-102% relative to the maximum response of 5-HT (serotonin)at a concentration of 1 μM.

1. A compound of the formula (I):

wherein R¹ is selected from H, C₁₋₄ alkyl, 2-hydroxyethyl, 2-cyanoethyl,tetrahydropyran-2-yl, and a nitrogen protecting group; R² and R³ each,independently, represent H or CH₃; R⁴ is selected from halogen, O—R⁵,NH—R⁵ or S—R⁵, wherein R⁵ is selected from aryl, aryl-C₁₋₆-alkyl,aryloxy-C₂₋₆-alkyl, heteroaryl, heteroaryl-C₁₋₆-alkyl,heteroaryloxy-C₂₋₆-alkyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₄-alkyl,C₁₋₆-alkyl, 2-tetrahydrofuryl, 3-tetrahydrofuryl, 2-tetrahydrofurfuryl,3-tetrahydrofurfuryl, piperidine-4-yl, tetrahydropyran-4-yl,C₃₋₆-alkynyl, C₃₋₆-alkenyl, or fluoro-C₂₋₄-alkyl; and wherein any arylor heteroaryl residue, alone or as part of another group, may beunsubstituted or substituted with one or more of C₁₋₄-alkyl,C₁₋₄-alkoxy, C₁₋₄-alkylthio, C₂₋₄-acyl, C₁₋₄-alkylsulphonyl, cyano,nitro, hydroxy, C₂₋₆-alkenyl, C₂₋₆-alkynyl, fluoromethyl,trifluoromethyl, trifluoromethoxy, halogen, —N(R⁶)(R⁷), aryl, aryloxy,arylthio, aryl-C₁₋₄-alkyl, aryl-C₂₋₄-alkenyl, aryl-C₂₋₄-alkynyl,heteroaryl, heteroaryloxy, heteroarylthio, heteroaryl-C₁₋₄-alkyl,aryl-C₁₋₄-alkoxy, aryloxy-C₁₋₄-alkyl, or dimethylamino-C₂₋₄-alkoxy,wherein R⁶ and R⁷ are, independently of each other, hydrogen, methyl orethyl; or form a pyrrolidine, piperazine, morpholine, thiomorpholine ora piperidine ring together with the nitrogen atom to which they arebound; and wherein any aryl or heteroaryl residue as substituents onaryl or heteroaryl, alone or as part of another group, in turn may besubstituted in one or more positions, preferably one, independently ofeach other by C₁₋₄-alkyl, C₁₋₄-alkoxy, halogen, trifluoromethyl, cyano,hydroxy or dimethylamino; and pharmaceutically acceptable salts,hydrates, solvates, geometrical isomers, tautomers, optical isomers,N-oxides and prodrug forms thereof, with the proviso that, when R⁴ ishalogen at least one of R¹, R², or R³ is not hydrogen.
 2. The compoundof claim 1, wherein R¹ is hydrogen.
 3. The compound of claim 1, whereinR⁴ is selected from chlorine, O—R⁵, and S—R⁵.
 4. The compound of claim3, wherein R⁵ is selected from aryl-C₁₋₆-alkyl, aryloxy-C₂₋₆-alkyl,heteroaryl-C₁₋₆-alkyl, heteroaryloxy-C₂₋₆-alkyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₄-alkyl, C₁₋₆-alkyl, 2-tetrahydrofurfuryl, andwherein any aryl or heteroaryl residue, alone or as part of anothergroup, may be unsubstituted or substituted with one or more ofC₁₋₄-alkyl, C₁₋₄-alkoxy, cyano, halogen, or aryloxy-C₁₋₄-alkyl.
 5. Thecompound of claim 4, wherein R⁵ is selected from benzyl, 2-chlorobenzyl,3-cyanobenzyl, 2-cyclohexylethyl, cyclopentyl, 2-cyclopentylethyl,2,3-difluorobenzyl, 2,6-difluorobenzyl, 2-(2,6-difluorophenoxy)ethyl,2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl, ethyl, 5-fluoro-2-methoxybenzyl,furan-2-ylmethyl, methyl, α-methylbenzyl, 3-methylbenzyl,2-(naphthalene-2-yloxy)ethyl, 2-phenoxyethyl, 2-phenoxymethylbenzyl,n-propyl, 3-(pyridin-3-yl)-n-propyl, 2-(8-quinolinyloxy)ethyl,tetrahydrofuran-2-ylmethyl, or 3-thienylmethyl.
 6. The compound of claim1, wherein the carbon atom, to which R² is attached, has the(S)-configuration when R² is methyl and R¹ and R3 both are hydrogen. 7.The compound of claim 1, wherein the carbon atom, to which R³ isattached, has the (R)-configuration when R³ is methyl and R¹ and R² bothare hydrogen
 8. The compound of claim 1, wherein the compound is1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-3-(S)-methyl-piperazine;1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-3-(R)-methylpiperazine;1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-2-(R)-methyl-piperazine;1-(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-2-(S)-methyl-piperazine,hydrochloride;1-[6-(2-Phenoxy-ethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate;1-[6-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate;1-[6-(Thiophen-3-ylmethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate;3-(6-Piperazin-1-yl-3-trifluoromethyl-pyridin-2-yloxymethyl)-benzonitrile,acetate;1-[6-(3-Methyl-benzylsulfanyl)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate;1-[6-(2-Chloro-benzylsulfanyl)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate;1-[6-(2,3-Difluoro-benzyloxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate; 1-(6-Ethylsulfanyl-5-trifluoromethyl-pyridin-2-yl)-piperazine,acetate; 1-(6-Propoxy-5-trifluoromethyl-pyridin-2-yl)-piperazine,acetate; 1-(6-Cyclopentyloxy-5-trifluoromethyl-pyridin-2-yl)-piperazine,acetate;1-[6-(1-Phenyl-ethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate;8-[2-(6-Piperazin-1-yl-3-trifluoromethyl-pyridin-2-yloxy)-ethoxy]-quinoline,acetate;1-[6-(2,6-Difluoro-benzyloxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate;1-[6-(3-{Pyridin-3-yl}propoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate; 1-(6-Benzyloxy-5-trifluoromethyl-pyridin-2-yl)-piperazine,acetate;1-[6-(Furan-2-ylmethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate;1-{6-[2-(2,6-Difluoro-phenoxy)-ethoxy]-5-trifluoromethyl-pyridin-2-yl}-piperazine,acetate;1-[6-(2-Chloro-benzylsulfanyl)-5-trifluoromethyl-pyridin-2-yl]-2-(R)-methyl-piperazine,acetate;1-(6-Ethylsulfanyl-5-trifluoromethyl-pyridin-2-yl)-3-(S)-methyl-piperazine,acetate;1-(6-Ethylsulfanyl-5-trifluoromethyl-pyridin-2-yl)-3-(R)-methyl-piperazine,acetate;1-(6-Ethylsulfanyl-5-trifluoromethyl-pyridin-2-yl)-2-(R)-methyl-piperazine,acetate;1-(6-Benzyloxy-5-trifluoromethyl-pyridin-2-yl)-3-(S)-methyl-piperazine,acetate;1-(6-Benzyloxy-5-trifluoromethyl-pyridin-2-yl)-3-(R)-methyl-piperazine,acetate;1-(6-Benzyloxy-5-trifluoromethyl-pyridin-2-yl)-2-(R)-methyl-piperazine,acetate;1-(6-Benzyloxy-5-trifluoromethyl-pyridin-2-yl)-2-(S)-methyl-piperazine,acetate; 1-(6-Methoxy-5-trifluoromethyl-pyridin-2-yl)-piperazine,acetate;1-[6-(5-Fluoro-2-methoxy-benzyloxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate;1-{6-[2-(Naphthalen-2-yloxy)-ethoxy]-5-trifluoromethyl-pyridin-2-yl}-piperazine,acetate;1-[6-(2-Chloro-benzylsulfanyl)-5-trifluoromethyl-pyridin-2-yl]-3-(S)-methyl-piperazine,acetate;1-[6-(2-Chloro-benzylsulfanyl)-5-trifluoromethyl-pyridin-2-yl]-2-(S)-methyl-piperazine,acetate;1-[6-(2-Phenoxymethyl-benzyloxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate;1-[6-Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate;1-[6-(2-Cyclopentyl-ethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate; or1-[6-(2-Cyclohexyl-ethoxy)-5-trifluoromethyl-pyridin-2-yl]-piperazine,acetate.
 9. A pharmaceutical composition comprising a compound offormula (I) of claim 1 and a pharmaceutically acceptable carrier.
 10. Amethod for the prophylaxis or treatment of a serotonin-related disorderor condition in a subject in need of such prophylaxis or treatment, themethod comprising administering to the subject an effective amount of acompound of formula (I) of claim
 1. 11. The method of claim 10, whereinthe serotonin-related disorder or condition is a 5-HT_(2c)receptor-related disorder or condition.
 12. The method of claim 11,wherein the 5-HT_(2c) receptor-related disorder or condition is selectedfrom memory disorders, Alzheimer's disease; schizophrenia; mooddisorders; anxiety disorders; pain; substance abuse; sexual dysfunction;epilepsy; glaucoma; urinary incontinence; menopausal and post-menopausalhot flushes; type II diabetes; eating disorders, binge eating disorders,anorexia nervosa, bulimia, or weight gain associated with antipsychoticdrug administration.
 13. The method of claim 11, wherein the the5-HT_(2c) receptor-related disorder or condition is obesity.
 14. Amethod for modulating 5-HT_(2c) receptor activity in a subject in needof such modulating, the method comprising administering to the subjectan effective amount of a compound of formula (I) of claim
 1. 15. Themethod of claim 10, wherein the subject is a human.
 16. The method ofclaim 10, wherein the subject is an animal.
 17. The method of claim 14,wherein the subject is an animal.
 18. The method of claim 14, whereinthe subject is a human.
 19. A method for preparing a pharmaceuticalcomposition, the method comprising combining a compound of formula (I)of claim 1 with a pharmaceutically acceptable carrier.
 20. A method ofmaking a compound of formula (I) of claim 1, by reacting a compound ofthe following formula (II):

wherein Hal is halogen; with an appropriate piperazine derivative offormula (III):

wherein R¹ is H or C₁₋₄ alkyl, 2-hydroxyethyl, 2-cyanoethyl,tetrahydropyran-2-yl, or a nitrogen protecting group; and R² and R³each, independently, represent H or CH₃; to produce a compound offormula (IV)

wherein R¹, R² and R³ have the same meaning as in formula (III); and Halis halogen, where the compound of formula (IV) is reacted with anappropriate alcohol, amine or thiol, as defined by O—R⁵, NH—R⁵ or S—R⁵,or its corresponding anions.